Health management devices and methods

ABSTRACT

Methods and devices and systems including a data collection module for receiving and storing analyte data over a predetermined time period from a subject, a user interface unit coupled to the data collection module for providing one or more indication related to the analyte data, a control unit coupled to the data collection module and the user interface unit to control, at least in part the operation of the data collection module and the user interface unit, a communication module coupled to the control unit for communicating one or more signals associated with the analyte data to a remote location, where the user interface unit is configured to operate in a prospective analysis mode including substantially real time output of the analyte level received by the data collection module, and a retrospective analysis mode including limited output of information to the subject during the predetermined time period, and further where the communication module is configured to communicate with the remote location after the analyte data is received and stored in the data collection module over the predetermined time period, are provided.

RELATED APPLICATION

The present application claims priority to U.S. provisional applicationNo. 60/945,579 filed Jun. 21, 2007, entitled “Health Management Devicesand Methods” and assigned to the assignee of the present application,Abbott Diabetes Care, Inc., the disclosure of which is incorporated byreference for all purposes.

BACKGROUND

The detection of the level of analytes, such as glucose, lactate,oxygen, and the like, in certain individuals is vitally important totheir health. For example, the monitoring of glucose is particularlyimportant to individuals with diabetes. Diabetics may need to monitorglucose levels to determine when insulin is needed to reduce glucoselevels in their bodies or when additional glucose is needed to raise thelevel of glucose in their bodies.

Accordingly, of interest are devices that allow a user to test for oneor more analytes.

SUMMARY

In accordance with embodiments of the present disclosure, there isprovided analyte monitoring methods and system for prospective orretrospective data analysis and processing including an in vivo analytemonitoring system comprising an analyte sensor and a module to collectanalyte data from the sensor for use by a first user, a data managementsystem to manipulate analyte data at a remote site, the analyte datatransferred to the data management system from the in vivo system, wherethe system is configured for use by at least a second user, and furtherwhere there is provided a patient privacy system to limit or restrictdata access by the type of users.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a block diagram of an embodiment of a data monitoring andmanagement system according to the present disclosure;

FIG. 2 shows a block diagram of an embodiment of the transmitter unit ofthe data monitoring and management system of FIG. 1;

FIG. 3 shows a block diagram of an embodiment of the receiver/monitorunit of the data monitoring and management system of FIG. 1;

FIG. 4 shows a schematic diagram of an embodiment of an analyte sensoraccording to the present disclosure;

FIGS. 5A-5B show a perspective view and a cross sectional view,respectively of another embodiment an analyte sensor;

FIGS. 6-10 illustrate exemplary blood glucose meters and test strips andusing the same;

FIG. 11 illustrates in vitro data transfer to a health care provider(HCP) via Universal Serial Bus (USB) connection to a computing devicesuch as a personal computer (PC) in one embodiment;

FIG. 12 illustrates prospective calibration of an assessor (AS) data,and unblinded assessor (AS) data in one embodiment;

FIG. 13 illustrates prospective calibration of the assessor (AS) data,unblinded data and associated analysis and an RF module in oneembodiment;

FIG. 14 illustrates unblinded, retrospective data and associatedanalysis and a USB connection in one embodiment;

FIG. 15 illustrates unblinded, prospective data and associated analysisand a wireless adapter in one embodiment; and

FIG. 16 shows a table of exemplary embodiments and respective featuresin one embodiment.

DETAILED DESCRIPTION

Before the present disclosure is described, it is to be understood thatthis disclosure is not limited to particular embodiments described, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present disclosure will be limited only by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges as also encompassed within the disclosure, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the disclosure.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure.

The figures shown herein are not necessarily drawn to scale, with somecomponents and features being exaggerated for clarity.

Generally, embodiments of the present disclosure relate to methods anddevices for detecting at least one analyte such as glucose in bodyfluid. Embodiments relate to the continuous and/or automatic in vivomonitoring of the level of one or more analytes using a continuousanalyte monitoring system that includes an analyte sensor at least aportion of which is to be positioned beneath a skin surface of a userfor a period of time and/or the discrete monitoring of one or moreanalytes using an in vitro blood glucose (“BG”) meter and an analytetest strip. Embodiments include combined or combinedable devices,systems and methods and/or transferring data between an in vivocontinuous system and a BG meter system.

Accordingly, embodiments include analyte monitoring devices and systemsthat include an analyte sensor—at least a portion of which ispositionable beneath the skin of the user—for the in vivo detection, ofan analyte, such as glucose, lactate, and the like, in a body fluid.Embodiments include wholly implantable analyte sensors and analytesensors in which only a portion of the sensor is positioned under theskin and a portion of the sensor resides above the skin, e.g., forcontact to a transmitter, receiver, transceiver, processor, etc. Thesensor may be, for example, subcutaneously positionable in a patient forthe continuous or periodic monitoring of a level of an analyte in apatient's interstitial fluid. For the purposes of this description,continuous monitoring and periodic monitoring will be usedinterchangeably, unless noted otherwise.

The sensor response may be correlated and/or converted to analyte levelsin blood or other fluids. In certain embodiments, an analyte sensor maybe positioned in contact with interstitial fluid to detect the level ofglucose, which detected glucose may be used to infer the glucose levelin the patient's bloodstream. Analyte sensors may be insertable into avein, artery, or other portion of the body containing fluid. Analytesensors that do not require bodily fluid contact are also contemplated.Embodiments of the analyte sensors may be configured for monitoring thelevel of the analyte over a time period which may range from minutes,hours, days, weeks, or longer.

Of interest are analyte sensors, such as glucose sensors, that arecapable of in vivo detection of an analyte for about one hour or more,e.g., about a few hours or more, e.g., about a few days of more, e.g.,about three or more days, e.g., about five days or more, e.g., aboutseven days or more, e.g., about several weeks or at least one month.Future analyte levels may be predicted based on information obtained,e.g., the current analyte level at time t₀, the rate of change of theanalyte, etc. Predictive alarms may notify the user of a predictedanalyte level that may be of concern in advance of the user's analytelevel reaching the future level. This provides the user an opportunityto take corrective action.

FIG. 1 shows a data monitoring and management system such as, forexample, an analyte (e.g., glucose) monitoring system 100 in accordancewith certain embodiments. Embodiments of the subject disclosure arefurther described primarily with respect to glucose monitoring devicesand systems, and methods of glucose detection, for convenience only andsuch description is in no way intended to limit the scope of thedisclosure. It is to be understood that the analyte monitoring systemmay be configured to monitor a variety of analytes at the same time orat different times.

Analytes that may be monitored include, but are not limited to acetylcholine, amylase, bilirubin, cholesterol, chorionic gonadotropin,creatine kinase (e.g., CK-MB), creatine, creatinine, DNA, fructosamine,glucose, glutamine, growth hormones, hormones, ketone bodies, lactate,peroxide, prostate-specific antigen, prothrombin, RNA, thyroidstimulating hormone, and troponin. The concentration of drugs, such as,for example, antibiotics (e.g., gentamicin, vancomycin, and the like),digitoxin, digoxin, drugs of abuse, theophylline, and warfarin, may alsobe monitored. In those embodiments that monitor more than one analyte,the analytes may be monitored at the same or different times.

The analyte monitoring system 100 includes a sensor 101, a dataprocessing unit or control unit 102 connectable to the sensor 101, and aprimary receiver unit 104 which is configured to communicate with thedata processing unit 102 via a communication link 103. In certainembodiments, the primary receiver unit 104 may be further configured totransmit data to a data processing terminal 105 to evaluate or otherwiseprocess or format data received by the primary receiver unit 104. Thedata processing terminal 105 may be configured to receive data directlyfrom the data processing unit 102 via a communication link which mayoptionally be configured for bi-directional communication. Further, thedata processing unit 102 may include a transmitter or a transceiver totransmit and/or receive data to and/or from the primary receiver unit104 and/or the data processing terminal 105 and/or optionally thesecondary receiver unit 106.

Also shown in FIG. 1 is an optional secondary receiver unit 106 which isoperatively coupled to the communication link and configured to receivedata transmitted from the data processing unit 102. The secondaryreceiver unit 106 may be configured to communicate with the primaryreceiver unit 104, as well as the data processing terminal 105. Thesecondary receiver unit 106 may be configured for bi-directionalwireless communication with each of the primary receiver unit 104 andthe data processing terminal 105. As discussed in further detail below,in certain embodiments the secondary receiver unit 106 may be ade-featured receiver as compared to the primary receiver, i.e., thesecondary receiver may include a limited or minimal number of functionsand features as compared with the primary receiver unit 104. As such,the secondary receiver unit 106 may include a smaller (in one or more,including all, dimensions), compact housing or embodied in a device suchas a wrist watch, arm band, etc., for example. Alternatively, thesecondary receiver unit 106 may be configured with the same orsubstantially similar functions and features as the primary receiverunit 104. The secondary receiver unit 106 may include a docking portionto be mated with a docking cradle unit for placement by, e.g., thebedside for night time monitoring, and/or a bi-directional communicationdevice. A docking cradle may recharge a power supply.

Only one sensor 101, data processing unit 102 and data processingterminal 105 are shown in the embodiment of the analyte monitoringsystem 100 illustrated in FIG. 1. However, it will be appreciated by oneof ordinary skill in the art that the analyte monitoring system 100 mayinclude more than one sensor 101 and/or more than one data processingunit 102, and/or more than one data processing terminal 105. Multiplesensors may be positioned in a patient for analyte monitoring at thesame or different times. In certain embodiments, analyte informationobtained by a first positioned sensor may be employed as a comparison toanalyte information obtained by a second sensor. This may be useful toconfirm or validate analyte information obtained from one or both of thesensors. Such redundancy may be useful if analyte information iscontemplated in critical therapy-related decisions. In certainembodiments, a first sensor may be used to calibrate a second sensor.

The analyte monitoring system 100 may be a continuous monitoring system,or semi-continuous, or a discrete monitoring system. In amulti-component environment, each component may be configured to beuniquely identified by one or more of the other components in the systemso that communication conflict may be readily resolved between thevarious components within the analyte monitoring system 100. Forexample, unique IDs, communication channels, and the like, may be used.

In certain embodiments, the sensor 101 is physically positioned in or onthe body of a user whose analyte level is being monitored. The sensor101 may be configured to at least periodically sample the analyte levelof the user and convert the sampled analyte level into a correspondingsignal for transmission by the data processing unit 102. The dataprocessing unit 102 is coupleable to the sensor 101 so that both devicesare positioned in or on the user's body, with at least a portion of theanalyte sensor 101 positioned transcutaneously. The data processing unitmay include a fixation element such as adhesive or the like to secure itto the user's body. A mount (not shown) attachable to the user andmateable with the unit 102 may be used. For example, a mount may includean adhesive surface. The data processing unit 102 performs dataprocessing functions, where such functions may include but are notlimited to, filtering and encoding of data signals, each of whichcorresponds to a sampled analyte level of the user, for transmission tothe primary receiver unit 104 via the communication link 103. In oneembodiment, the sensor 101 or the data processing unit 102 or a combinedsensor/data processing unit may be wholly implantable under the skinlayer of the user.

In certain embodiments, the primary receiver unit 104 may include ananalog interface section including an RF receiver and an antenna that isconfigured to communicate with the data processing unit 102 via thecommunication link 103, and a data processing section for processing thereceived data from the data processing unit 102 such as data decoding,error detection and correction, data clock generation, data bitrecovery, etc., or any combination thereof.

In operation, the primary receiver unit 104 in certain embodiments isconfigured to synchronize with the data processing unit 102 to uniquelyidentify the data processing unit 102, based on, for example, anidentification information of the data processing unit 102, andthereafter, to periodically receive signals transmitted from the dataprocessing unit 102 associated with the monitored analyte levelsdetected by the sensor 101.

Referring again to FIG. 1, the data processing terminal 105 may includea personal computer, a portable computer such as a laptop or a handhelddevice (e.g., personal digital assistants (PDAs), telephone such as acellular phone (e.g., a multimedia and Internet-enabled mobile phonesuch as an iPhone or similar phone), mp3 player, pager, and the like),drug delivery device, each of which may be configured for datacommunication with the receiver via a wired or a wireless connection.Additionally, the data processing terminal 105 may further be connectedto a data network (not shown) for storing, retrieving, updating, and/oranalyzing data corresponding to the detected analyte level of the user.

The data processing terminal 105 may include an infusion device such asan insulin infusion pump or the like, which may be configured toadminister insulin to patients, and which may be configured tocommunicate with the primary receiver unit 104 for receiving, amongothers, the measured analyte level. Alternatively, the primary receiverunit 104 may be configured to integrate an infusion device therein sothat the primary receiver unit 104 is configured to administer insulin(or other appropriate drug) therapy to patients, for example, foradministering and modifying basal profiles, as well as for determiningappropriate boluses for administration based on, among others, thedetected analyte levels received from the data processing unit 102. Aninfusion device may be an external device or an internal device (whollyimplantable in a user).

In certain embodiments, the data processing terminal 105, which mayinclude an insulin pump, may be configured to receive the analytesignals from the data processing unit 102, and thus, incorporate thefunctions of the primary receiver unit 104 including data processing formanaging the patient's insulin therapy and analyte monitoring. Incertain embodiments, the communication link 103 as well as one or moreof the other communication interfaces shown in FIG. 1, may use one ormore of: an RF communication protocol, an infrared communicationprotocol, a Bluetooth® enabled communication protocol, an 802.11xwireless communication protocol, or an equivalent wireless communicationprotocol which would allow secure, wireless communication of severalunits (for example, per HIPAA requirements), while avoiding potentialdata collision and interference.

FIG. 2 shows a block diagram of an embodiment of a data processing unitof the data monitoring and detection system shown in FIG. 1. User inputand/or interface components may be included or a data processing unitmay be free of user input and/or interface components. In certainembodiments, one or more application-specific integrated circuits (ASIC)may be used to implement one or more functions or routines associatedwith the operations of the data processing unit (and/or receiver unit)using for example one or more state machines and buffers.

As can be seen in the embodiment of FIG. 2, the sensor unit 101 (FIG. 1)includes four contacts, three of which are electrodes—work electrode (W)210, reference electrode (R) 212, and counter electrode (C) 213, eachoperatively coupled to the analog interface 201 of the data processingunit 102. This embodiment also shows optional guard contact (G) 211.Fewer or greater electrodes may be employed. For example, the counterand reference electrode functions may be served by a singlecounter/reference electrode, there may be more than one workingelectrode and/or reference electrode and/or counter electrode, and soon. The processor shown in FIG. 2 may be equipped with sufficient memoryto store the data of interest (such as analyte data) for extendedperiods of time ranging from one to several samples to the number ofsamples obtained for an entire wear period of several days to weeks. Inone aspect, the memory may be included as part of the processor 204. Inanother embodiment, a separate memory unit such as a memory chip, randomaccess memory (RAM) or any other storage device for storing forsubsequent retrieval data.

FIG. 3 is a block diagram of an embodiment of a receiver/monitor unitsuch as the primary receiver unit 104 of the data monitoring andmanagement system shown in FIG. 1. The primary receiver unit 104includes one or more of: a blood glucose test strip interface 301, an RFreceiver 302, an input 303, a temperature detection section 304, and aclock 305, each of which is operatively coupled to a processing andstorage section 307. The primary receiver unit 104 also includes a powersupply 306 operatively coupled to a power conversion and monitoringsection 308. Further, the power conversion and monitoring section 308 isalso coupled to the receiver processor 307. Moreover, also shown are areceiver serial communication section 309, and an output 310, eachoperatively coupled to the processing and storage unit 307. The receivermay include user input and/or interface components or may be free ofuser input and/or interface components.

In certain embodiments, the test strip interface 301 includes a glucoselevel testing portion to receive a blood (or other body fluid sample)glucose test or information related thereto. For example, the interfacemay include a test strip port to receive a glucose test strip. Thedevice may determine the glucose level of the test strip, and optionallydisplay (or otherwise notice) the glucose level on the output 310 of theprimary receiver unit 104. Any suitable test strip may be employed,e.g., test strips that only require a very small amount (e.g., onemicroliter or less, e.g., 0.5 microliter or less, e.g., 0.1 microliteror less), of applied sample to the strip in order to obtain accurateglucose information, e.g. FreeStyle® blood glucose test strips fromAbbott Diabetes Care, Inc. Glucose information obtained by the in vitroglucose testing device may be used for a variety of purposes,computations, etc. For example, the information may be used to calibratesensor 101, confirm results of the sensor 101 to increase the confidencethereof (e.g., in instances in which information obtained by sensor 101is employed in therapy related decisions), and the like.

In further embodiments, the data processing unit 102 and/or the primaryreceiver unit 104 and/or the secondary receiver unit 106, and/or thedata processing terminal/infusion section 105 may be configured toreceive the blood glucose value wirelessly (or via a wire as shown inFIG. 12) over a communication link from, for example, a blood glucosemeter. In further embodiments, a user manipulating or using the analytemonitoring system 100 (FIG. 1) may manually input the blood glucosevalue using, for example, a user interface (for example, a keyboard,keypad, voice commands, and the like) incorporated in one or more of thedata processing unit 102, the primary receiver unit 104, secondaryreceiver unit 106, or the data processing terminal/infusion section 105.

Additional detailed description of embodiments of test strips, bloodglucose (BG) meters and continuous monitoring systems and datamanagement systems that may be employed are provided in but not limitedto: U.S. Pat. Nos. 6,175,752; 6,560,471; 5,262,035; 6,881,551;6,121,009; 7,167,818; 6,270,455; 6,161,095; 5,918,603; 6,144,837;5,601,435; 5,822,715; 5,899,855; 6,071,391; 6,120,676; 6,143,164;6,299,757; 6,338,790; 6,377,894; 6,600,997; 6,773,671; 6,514,460;6,592,745; 5,628,890; 5,820,551; 6,736,957; 4,545,382; 4,711,245;5,509,410; 6,540,891; 6,730,200; 6,764,581; 6,299,757; 6,461,496;6,503,381; 6,591,125; 6,616,819; 6,618,934; 6,676,816; 6,749,740;6,893,545; 6,942,518; 6,514,718; U.S. patent application Ser. No.10/745,878 filed Dec. 26, 2003 entitled “Continuous Glucose MonitoringSystem and Methods of Use”, and elsewhere, the disclosures of each whichare incorporated herein by reference for all purposes.

FIG. 4 schematically shows an embodiment of an analyte sensor inaccordance with the present disclosure. This sensor embodiment includeselectrodes 401, 402 and 403 on a base 404. Electrodes (and/or otherfeatures) may be applied or otherwise processed using any suitabletechnology, e.g., chemical vapor deposition (CVD), physical vapordeposition, sputtering, reactive sputtering, printing, coating, ablating(e.g., laser ablation), painting, dip coating, etching, and the like.Materials include but are not limited to aluminum, carbon (such asgraphite), cobalt, copper, gallium, gold, indium, iridium, iron, lead,magnesium, mercury (as an amalgam), nickel, niobium, osmium, palladium,platinum, rhenium, rhodium, selenium, silicon (e.g., dopedpolycrystalline silicon), silver, tantalum, tin, titanium, tungsten,uranium, vanadium, zinc, zirconium, mixtures thereof, and alloys,oxides, or metallic compounds of these elements.

The sensor may be wholly implantable in a user or may be configured sothat only a portion is positioned within (internal) a user and anotherportion outside (external) a user. For example, the sensor 400 mayinclude a portion positionable above a surface of the skin 410, and aportion positioned below the skin. In such embodiments, the externalportion may include contacts (connected to respective electrodes of thesecond portion by traces) to connect to another device also external tothe user such as a transmitter unit. While the embodiment of FIG. 4shows three electrodes side-by-side on the same surface of base 404,other configurations are contemplated, e.g., fewer or greaterelectrodes, some or all electrodes on different surfaces of the base orpresent on another base, some or all electrodes stacked together,electrodes of differing materials and dimensions, etc.

FIG. 5A shows a perspective view of an embodiment of an electrochemicalanalyte sensor 500 having a first portion (which in this embodiment maybe characterized as a major portion) positionable above a surface of theskin 510, and a second portion (which in this embodiment may becharacterized as a minor portion) that includes an insertion tip 530positionable below the skin, e.g., penetrating through the skin andinto, e.g., the subcutaneous space 520, in contact with the user'sbiofluid such as interstitial fluid. Contact portions of a workingelectrode 501, a reference electrode 502, and a counter electrode 503are positioned on the portion of the sensor 500 situated above the skinsurface 510. Working electrode 501, a reference electrode 502, and acounter electrode 503 are shown at the second section and particularlyat the insertion tip 530. Traces may be provided from the electrode atthe tip to the contact, as shown in FIG. 5A. It is to be understood thatgreater or fewer electrodes may be provided on a sensor. For example, asensor may include more than one working electrode and/or the counterand reference electrodes may be a single counter/reference electrode,etc.

FIG. 5B shows a cross sectional view of a portion of the sensor 500 ofFIG. 5A. The electrodes 510, 502 and 503, of the sensor 500 as well asthe substrate and the dielectric layers are provided in a layeredconfiguration or construction. For example, as shown in FIG. 5B, in oneaspect, the sensor 500 (such as the sensor unit 101 FIG. 1), includes asubstrate layer 504, and a first conducting layer 501 such as carbon,gold, etc., disposed on at least a portion of the substrate layer 504,and which may provide the working electrode. Also shown disposed on atleast a portion of the first conducting layer 501 is a sensing layer508.

A first insulation layer such as a first dielectric layer 505 isdisposed or layered on at least a portion of the first conducting layer501, and further, a second conducting layer 509 may be disposed orstacked on top of at least a portion of the first insulation layer (ordielectric layer) 505. As shown in FIG. 5B, the second conducting layer509 may provide the reference electrode 502, and in one aspect, mayinclude a layer of silver/silver chloride (Ag/AgCl), gold, etc.

A second insulation layer 506 such as a dielectric layer in oneembodiment may be disposed or layered on at least a portion of thesecond conducting layer 509. Further, a third conducting layer 503 mayprovide the counter electrode 503. It may be disposed on at least aportion of the second insulation layer 506. Finally, a third insulationlayer may be disposed or layered on at least a portion of the thirdconducting layer 503. In this manner, the sensor 500 may be layered suchthat at least a portion of each of the conducting layers is separated bya respective insulation layer (for example, a dielectric layer). Theembodiment of FIGS. 5A and 5B show the layers having different lengths.Some or all of the layers may have the same or different lengths and/orwidths.

In certain embodiments, some or all of the electrodes 501, 502, 503 maybe provided on the same side of the substrate 504 in the layeredconstruction as described above, or alternatively, may be provided in aco-planar manner such that two or more electrodes may be positioned onthe same plane (e.g., side-by side (e.g., parallel) or angled relativeto each other) on the substrate 504. For example, co-planar electrodesmay include a suitable spacing there between and/or include dielectricmaterial or insulation material disposed between the conductinglayers/electrodes. Furthermore, in certain embodiments, one or more ofthe electrodes 501, 502, 503 may be disposed on opposing sides of thesubstrate 504. In such embodiments, contact pads may be on the same ordifferent sides of the substrate. For example, an electrode may be on afirst side and its respective contact may be on a second side, e.g., atrace connecting the electrode and the contact may traverse through thesubstrate.

As noted above, analyte sensors may include an analyte-responsive enzymeto provide a sensing component or sensing layer. Some analytes, such asoxygen, can be directly electrooxidized or electroreduced on a sensor,and more specifically at least on a working electrode of a sensor. Otheranalytes, such as glucose and lactate, require the presence of at leastone electron transfer agent and/or at least one catalyst to facilitatethe electrooxidation or electroreduction of the analyte. Catalysts mayalso be used for those analytes, such as oxygen, that can be directlyelectrooxidized or electroreduced on the working electrode. For theseanalytes, each working electrode includes a sensing layer (see forexample sensing layer 508 of FIG. 5B) proximate to or on a surface of aworking electrode. In many embodiments, a sensing layer is formed nearor on only a small portion of at least a working electrode.

The sensing layer includes one or more components designed to facilitatethe electrochemical oxidation or reduction of the analyte. The sensinglayer may include, for example, a catalyst to catalyze a reaction of theanalyte and produce a response at the working electrode, an electrontransfer agent to transfer electrons between the analyte and the workingelectrode (or other component), or both.

A variety of different sensing layer configurations may be used. Incertain embodiments, the sensing layer is deposited on the conductivematerial of a working electrode. The sensing layer may extend beyond theconductive material of the working electrode. In some cases, the sensinglayer may also extend over other electrodes, e.g., over the counterelectrode and/or reference electrode (or counter/reference is provided).

A sensing layer that is in direct contact with the working electrode maycontain an electron transfer agent to transfer electrons directly orindirectly between the analyte and the working electrode, and/or acatalyst to facilitate a reaction of the analyte. For example, aglucose, lactate, or oxygen electrode may be formed having a sensinglayer which contains a catalyst, such as glucose oxidase, lactateoxidase, or laccase, respectively, and an electron transfer agent thatfacilitates the electrooxidation of the glucose, lactate, or oxygen,respectively.

In other embodiments the sensing layer is not deposited directly on theworking electrode. Instead, the sensing layer 508 may be spaced apartfrom the working electrode, and separated from the working electrode,e.g., by a separation layer. A separation layer may include one or moremembranes or films or a physical distance. In addition to separating theworking electrode from the sensing layer the separation layer may alsoact as a mass transport limiting layer and/or an interferent eliminatinglayer and/or a biocompatible layer.

In certain embodiments which include more than one working electrode,one or more of the working electrodes may not have a correspondingsensing layer, or may have a sensing layer which does not contain one ormore components (e.g., an electron transfer agent and/or catalyst)needed to electrolyze the analyte. Thus, the signal at this workingelectrode may correspond to background signal which may be removed fromthe analyte signal obtained from one or more other working electrodesthat are associated with fully-functional sensing layers by, forexample, subtracting the signal.

In certain embodiments, the sensing layer includes one or more electrontransfer agents. Electron transfer agents that may be employed areelectroreducible and electrooxidizable ions or molecules having redoxpotentials that are a few hundred millivolts above or below the redoxpotential of the standard calomel electrode (SCE). The electron transferagent may be organic, organometallic, or inorganic. Examples of organicredox species are quinones and species that in their oxidized state havequinoid structures, such as Nile blue and indophenol. Examples oforganometallic redox species are metallocenes such as ferrocene.Examples of inorganic redox species are hexacyanoferrate (III),ruthenium hexamine etc.

In certain embodiments, electron transfer agents have structures orcharges which prevent or substantially reduce the diffusional loss ofthe electron transfer agent during the period of time that the sample isbeing analyzed. For example, electron transfer agents include but arenot limited to a redox species, e.g., bound to a polymer which can inturn be disposed on or near the working electrode. The bond between theredox species and the polymer may be covalent, coordinative, or ionic.Although any organic, organometallic or inorganic redox species may bebound to a polymer and used as an electron transfer agent, in certainembodiments the redox species is a transition metal compound or complex,e.g., osmium, ruthenium, iron, and cobalt compounds or complexes. Itwill be recognized that many redox species described for use with apolymeric component may also be used, without a polymeric component.

One type of polymeric electron transfer agent contains a redox speciescovalently bound in a polymeric composition. An example of this type ofmediator is poly(vinylferrocene). Another type of electron transferagent contains an ionically-bound redox species. This type of mediatormay include a charged polymer coupled to an oppositely charged redoxspecies. Examples of this type of mediator include a negatively chargedpolymer coupled to a positively charged redox species such as an osmiumor ruthenium polypyridyl cation. Another example of an ionically-boundmediator is a positively charged polymer such as quaternizedpoly(4-vinyl pyridine) or poly(1-vinyl imidazole) coupled to anegatively charged redox species such as ferricyanide or ferrocyanide.In other embodiments, electron transfer agents include a redox speciescoordinatively bound to a polymer. For example, the mediator may beformed by coordination of an osmium or cobalt 2,2′-bipyridyl complex topoly(1-vinyl imidazole) or poly(4-vinyl pyridine).

Suitable electron transfer agents are osmium transition metal complexeswith one or more ligands, each ligand having a nitrogen-containingheterocycle such as 2,2′-bipyridine, 1,10-phenanthroline, 1-methyl,2-pyridyl biimidazole, or derivatives thereof. The electron transferagents may also have one or more ligands covalently bound in a polymer,each ligand having at least one nitrogen-containing heterocycle, such aspyridine, imidazole, or derivatives thereof One example of an electrontransfer agent includes (a) a polymer or copolymer having pyridine orimidazole functional groups and (b) osmium cations complexed with twoligands, each ligand containing 2,2′-bipyridine, 1,10-phenanthroline, orderivatives thereof, the two ligands not necessarily being the same.Some derivatives of 2,2′-bipyridine for complexation with the osmiumcation include but are not limited to 4,4′-dimethyl-2,2′-bipyridine andmono-, di-, and polyalkoxy-2,2′-bipyridines, such as4,4′-dimethoxy-2,2′-bipyridine. Derivatives of 1,10-phenanthroline forcomplexation with the osmium cation include but are not limited to4,7-dimethyl-1,10-phenanthroline and mono, di-, andpolyalkoxy-1,10-phenanthrolines, such as4,7-dimethoxy-1,10-phenanthroline. Polymers for complexation with theosmium cation include but are not limited to polymers and copolymers ofpoly(1-vinyl imidazole) (referred to as “PVI”) and poly(4-vinylpyridine) (referred to as “PVP”). Suitable copolymer substituents ofpoly(1-vinyl imidazole) include acrylonitrile, acrylamide, andsubstituted or quatemized N-vinyl imidazole, e.g., electron transferagents with osmium complexed to a polymer or copolymer of poly(1-vinylimidazole).

Embodiments may employ electron transfer agents having a redox potentialranging from about −200 mV to about +200 mV versus the standard calomelelectrode (SCE). The sensing layer may also include a catalyst which iscapable of catalyzing a reaction of the analyte. The catalyst may also,in some embodiments, act as an electron transfer agent. One example of asuitable catalyst is an enzyme which catalyzes a reaction of theanalyte. For example, a catalyst, such as a glucose oxidase, glucosedehydrogenase (e.g., pyrroloquinoline quinone (PQQ), dependent glucosedehydrogenase, flavine adenine dinucleotide (FAD) dependent glucosedehydrogenase, or nicotinamide adenine dinucleotide (NAD) dependentglucose dehydrogenase), may be used when the analyte of interest isglucose. A lactate oxidase or lactate dehydrogenase may be used when theanalyte of interest is lactate. Laccase may be used when the analyte ofinterest is oxygen or when oxygen is generated or consumed in responseto a reaction of the analyte.

The sensing layer may also include a catalyst which is capable ofcatalyzing a reaction of the analyte. The catalyst may also, in someembodiments, act as an electron transfer agent. One example of asuitable catalyst is an enzyme which catalyzes a reaction of theanalyte. For example, a catalyst, such as a glucose oxidase, glucosedehydrogenase (e.g., pyrroloquinoline quinone (PQQ), dependent glucosedehydrogenase or oligosaccharide dehydrogenase, flavine adeninedinucleotide (FAD) dependent glucose dehydrogenase, nicotinamide adeninedinucleotide (NAD) dependent glucose dehydrogenase), may be used whenthe analyte of interest is glucose. A lactate oxidase or lactatedehydrogenase may be used when the analyte of interest is lactate.Laccase may be used when the analyte of interest is oxygen or whenoxygen is generated or consumed in response to a reaction of theanalyte.

In certain embodiments, a catalyst may be attached to a polymer, crosslinking the catalyst with another electron transfer agent (which, asdescribed above, may be polymeric. A second catalyst may also be used incertain embodiments. This second catalyst may be used to catalyze areaction of a product compound resulting from the catalyzed reaction ofthe analyte. The second catalyst may operate with an electron transferagent to electrolyze the product compound to generate a signal at theworking electrode. Alternatively, a second catalyst may be provided inan interferent-eliminating layer to catalyze reactions that removeinterferents.

Certain embodiments include a Wired Enzyme™ sensing layer (AbbottDiabetes Care, Inc.) that works at a gentle oxidizing potential, e.g., apotential of about +40 mV. This sensing layer uses an osmium (Os)-basedmediator designed for low potential operation and is stably anchored ina polymeric layer. Accordingly, in certain embodiments the sensingelement is redox active component that includes (1) Osmium-basedmediator molecules attached by stable (bidente) ligands anchored to apolymeric backbone, and (2) glucose oxidase enzyme molecules. These twoconstituents are crosslinked together.

A mass transport limiting layer (not shown), e.g., an analyte fluxmodulating layer, may be included with the sensor to act as adiffusion-limiting barrier to reduce the rate of mass transport of theanalyte, for example, glucose or lactate, into the region around theworking electrodes. The mass transport limiting layers are useful inlimiting the flux of an analyte to a working electrode in anelectrochemical sensor so that the sensor is linearly responsive over alarge range of analyte concentrations and is easily calibrated. Masstransport limiting layers may include polymers and may be biocompatible.A mass transport limiting layer may provide many functions, e.g.,biocompatibility and/or interferent-eliminating, etc.

In certain embodiments, a mass transport limiting layer is a membranecomposed of crosslinked polymers containing heterocyclic nitrogengroups, such as polymers of polyvinylpyridine and polyvinylimidazole.Embodiments also include membranes that are made of a polyurethane, orpolyether urethane, or chemically related material, or membranes thatare made of silicone, and the like.

A membrane may be formed by crosslinking in situ a polymer, modifiedwith a zwitterionic moiety, a non-pyridine copolymer component, andoptionally another moiety that is either hydrophilic or hydrophobic,and/or has other desirable properties, in an alcohol-buffer solution.The modified polymer may be made from a precursor polymer containingheterocyclic nitrogen groups. For example, a precursor polymer may bepolyvinylpyridine or polyvinylimidazole. Optionally, hydrophilic orhydrophobic modifiers may be used to “fine-tune” the permeability of theresulting membrane to an analyte of interest. Optional hydrophilicmodifiers, such as poly(ethylene glycol), hydroxyl or polyhydroxylmodifiers, may be used to enhance the biocompatibility of the polymer orthe resulting membrane.

A membrane may be formed in situ by applying an alcohol-buffer solutionof a crosslinker and a modified polymer over an enzyme-containingsensing layer and allowing the solution to cure for about one to twodays or other appropriate time period. The crosslinker-polymer solutionmay be applied to the sensing layer by placing a droplet or droplets ofthe solution on the sensor, by dipping the sensor into the solution, orthe like. Generally, the thickness of the membrane is controlled by theconcentration of the solution, by the number of droplets of the solutionapplied, by the number of times the sensor is dipped in the solution, orby any combination of these factors. A membrane applied in this mannermay have any combination of the following functions: (1) mass transportlimitation, i.e. reduction of the flux of analyte that can reach thesensing layer, (2) biocompatibility enhancement, or (3) interferentreduction.

The description herein is directed primarily to electrochemical sensorsfor convenience only and is in no way intended to limit the scope of thedisclosure. Other sensors and sensor systems are contemplated. Suchinclude, but are not limited to, optical sensors, colorimetric sensors,and sensors that detect hydrogen peroxide to infer glucose levels,potentiometric sensors, coulometric sensors, or oxygen sensors.

For example, a hydrogen peroxide-detecting sensor may be constructed inwhich a sensing layer includes enzyme such as glucose oxides, glucosedehydrogensae, or the like, and is positioned proximate to the workingelectrode. The sending layer may be covered by a membrane that isselectively permeable to glucose. Once the glucose passes through themembrane, it is oxidized by the enzyme and reduced glucose oxidase canthen be oxidized by reacting with molecular oxygen to produce hydrogenperoxide.

Certain embodiments include a hydrogen peroxide-detecting sensorconstructed from a sensing layer prepared by crosslinking two componentstogether, for example: (1) a redox compound such as a redox polymercontaining pendent Os polypyridyl complexes with oxidation potentials ofabout +200 mV vs. SCE, and (2) periodate oxidized horseradish peroxidase(HRP). Such a sensor functions in a reductive mode; the workingelectrode is controlled at a potential negative to that of the Oscomplex, resulting in mediated reduction of hydrogen peroxide throughthe HRP catalyst.

In another example, a potentiometric sensor can be constructed asfollows. A glucose-sensing layer is constructed by crosslinking together(1) a redox polymer containing pendent Os polypyridyl complexes withoxidation potentials from about −200 mV to +200 mV vs. SCE, and (2)glucose oxidase. This sensor can then be used in a potentiometric mode,by exposing the sensor to a glucose containing solution, underconditions of zero current flow, and allowing the ratio ofreduced/oxidized Os to reach an equilibrium value. The reduced/oxidizedOs ratio varies in a reproducible way with the glucose concentration,and will cause the electrode's potential to vary in a similar way.

A sensor may also include an active agent such as an anticlotting and/orantiglycolytic agent(s) disposed on at least a portion a sensor that ispositioned in a user. An anticlotting agent may reduce or eliminate theclotting of blood or other body fluid around the sensor, particularlyafter insertion of the sensor. Examples of useful anticlotting agentsinclude heparin and tissue plasminogen activator (TPA), as well as otherknown anticlotting agents. Embodiments may include an antiglycolyticagent or precursor thereof. Examples of antiglycolytic agents areglyceraldehyde, fluoride ion, and mannose.

Sensors may be configured to require no system calibration or no usercalibration. For example, a sensor may be factory calibrated and may notrequire further calibration during the life of the sensor. In certainembodiments, calibration may be required, but may be done without userintervention, i.e., may be automatic. In those embodiments in whichcalibration by the user is required, the calibration may be according toa predetermined schedule or may be dynamic, i.e., the time for which maybe determined by the system on a real-time basis according to variousfactors, such as but not limited to glucose concentration and/ortemperature and/or rate of change of glucose, etc.

Calibration may be accomplished using an in vitro test strip (or otherreference), e.g., a small sample test strip such as a test strip thatrequires less than about 1 microliter of sample (for example FreeStyle®blood glucose monitoring test strips from Abbott Diabetes Care, Inc.).For example, test strips that require less than about 1 nanoliter ofsample may be used. In certain embodiments, a sensor may be calibratedusing only one sample of body fluid per calibration event. For example,a user need only lance a body part one time to obtain sample for acalibration event (e.g., for a test strip), or may lance more than onetime within a short period of time if an insufficient volume of sampleis firstly obtained. Embodiments include obtaining and using multiplesamples of body fluid for a given calibration event, where glucosevalues of each sample are substantially similar. Data obtained from agiven calibration event may be used independently to calibrate orcombine with data obtained from previous calibration events, e.g.,averaged including weighted averaged, etc., to calibrate. In certainembodiments, a system need only be calibrated once by a user, whererecalibration of the system is not required.

Analyte systems may include an optional alarm system that, e.g., basedon information from a processor, warns the patient of a potentiallydetrimental condition of the analyte. For example, if glucose is theanalyte, an alarm system may warn a user of conditions such ashypoglycemia and/or hyperglycemia and/or impending hypoglycemia, and/orimpending hyperglycemia. An alarm system may be triggered when analytelevels approach, reach or exceed a threshold value. An alarm system mayalso, or alternatively, be activated when the rate of change, oracceleration of the rate of change, in analyte level increase ordecrease approaches, reaches or exceeds a threshold rate oracceleration. A system may also include system alarms that notify a userof system information such as battery condition, calibration, sensordislodgment, sensor malfunction, etc. Alarms may be, for example,auditory and/or visual. Other sensory-stimulating alarm systems may beused including alarm systems which heat, cool, vibrate, or produce amild electrical shock when activated.

The subject disclosure also includes sensors used in sensor-based drugdelivery systems. The system may provide a drug to counteract the highor low level of the analyte in response to the signals from one or moresensors. Alternatively, the system may monitor the drug concentration toensure that the drug remains within a desired therapeutic range. Thedrug delivery system may include one or more (e.g., two or more)sensors, a processing unit such as a transmitter, a receiver/displayunit, and a drug administration system. In some cases, some or allcomponents may be integrated in a single unit. A sensor-based drugdelivery system may use data from the one or more sensors to providenecessary input for a control algorithm/mechanism to adjust theadministration of drugs, e.g., automatically or semi-automatically. Asan example, a glucose sensor may be used to control and adjust theadministration of insulin from an external or implanted insulin pump.

In certain embodiments, a continuous glucose (“CG”) monitoring system(for example a FreeStyle Navigator® continuous glucose monitoring systemor certain components thereof) may be used to assess diabetes andtreatment options, e.g., assessed by a health care provider (“HCP”)device. Such an assessment may occur at initial phases of, or at thebeginning of diagnosis or onset of, diabetic condition. A CG system maybe provided to a user to monitor glucose levels for a period of time,e.g., about one day to about one month or more, e.g., about a few daysto about a few weeks, e.g., about 1-2 weeks. The information gathered bythe CG system may be reviewed retrospectively by an HCP, e.g., stored inan HCP device memory and communicated to (including transferred to) HCP,to assess the next steps of treating and/or monitoring the user'sglucose levels to control diabetes. These CG systems may generally bereferred to as “assessor” (“AS”) systems. Generally, a CG system is anin vivo system, e.g., that a user may borrow/rent/otherwise obtainwhenever they are collecting glucose data.

In certain embodiments, an HCP may use AS system data obtained from auser to assess whether the user would benefit from using an in vitrometer (test strip and meter, including an integrated glucose monitoringsystem). The HCP may then prescribe such a system for the user. Ofcourse, an HCP may determine that the user continue to use an in vivosystem or that no additional glucose monitoring is required. In manyembodiments, an HCP may determine (and prescribe) a short assaytime/small sample size in vitro system, and a user may monitor theirglucose levels using such a system. Accordingly, after using an ASsystem to monitor glucose levels for a period of time, an HCP may, afterreviewing the AS data obtained during this time, recommend that the userto continue to monitor glucose levels using an in vitro system.Typically (though not always) the user may use the in vitro system asthe primary and sole source of glucose monitoring, i.e., the AS systemneed not be used by the user any longer, or may be used periodically.

In certain embodiments, a given AS system may be used to monitor glucoselevels of a first person, an HCP may review the data therefrom, and theAS system may then be used by at least a second person (excluding theanalyte sensor).

As noted above, an HCP may recommend (and prescribe) an in vitro systemfor a user if AS data reviewed by the HCP after being used for a periodof time indicates that such a system would be beneficial for theuser/patient.

Embodiments include devices which allow diabetics or users evaluatingwhether they have diabetes to measure the blood (or other bodily fluid)glucose levels, e.g., hand-held electronic meters (blood glucosemeters), e.g., such as Freestyle® or Precision® blood glucose monitoringsystems available from Abbott Diabetes Care, Inc., of Alameda, Calif.which receives blood samples via enzyme-based test strips. Typically, auser inserts a test strip into a meter and lances a finger or alternatebody site to obtain a blood sample. The drawn sample is applied to thetest strip and the meter reads the strip and determines analyteconcentration, which is then conveyed to the user. For example, a bloodglucose meter may convert a current generated by the enzymatic reactionin the test strip to a corresponding blood glucose value which isdisplayed or otherwise provided to the patient to show the level ofglucose at the time of testing. Such periodic discrete glucose testinghelps diabetic patients to take any necessary corrective actions tobetter manage diabetic conditions.

Test strips for use with such in vitro systems may be adapted to measurethe concentration of an analyte in any volume of sample, including butnot limited to small volumes of sample, e.g., about 1 microliter or lesssample, for example about 0.5 microliters or less, for example about 0.3microliters or less, for example about 0.1 microliters or less. In someembodiments, the volume of sample may be as low as about 0.05microliters or as low as about 0.03 microliters. Strips may beconfigured so that an accurate analyte measurement may be obtained usinga volume of sample that wholly or partially fills a sample chamber of astrip. In certain embodiments, a test may only start when sufficientsample has been applied to a strip, e.g., as detected by a detector suchas an electrode. An in vitro system may be programmed to allowre-application of additional sample if insufficient sample is firstlyapplied, e.g., the time to reapply sample may range from about 10seconds to about 2 minutes, e.g., from about 30 seconds to about 60seconds.

Strips may be side fill, front fill, top fill or corner fill, or anycombination thereof Test strips may be calibration-free, e.g., minimalinput (if any) is required of a user to calibrate. In certainembodiments, no calibration test strips may be employed. In suchembodiments, the user need not take any action for calibration, i.e.,calibration is invisible to a user.

As noted above, strips are used with meters. In certain embodiments,meters may be integrated meters, i.e., a device which has at least onestrip and at least a second element, such as a meter and/or a skinpiercing element such as a lancet or the like, in the device. In someembodiments, a strip may be integrated with both a meter and a lancet,e.g., in a single housing. Having multiple elements together in onedevice reduces the number of devices needed to obtain an analyte leveland facilitates the sampling process. For example, embodiments mayinclude a housing that includes one or more analyte test strips, a skinpiercing element and a processor for determining the concentration of ananalyte in a sample applied to the strip. A plurality of strips may beretained in a magazine in the housing interior and, upon actuation by auser, a single strip may be dispensed from the magazine so that at leasta portion extends out of the housing for use.

Test strips may be short test time test strips. For example, test timesmay range from about 1 second to about 20 seconds, e.g., from about 3seconds to about 10 seconds, e.g., from about 3 seconds to about 7seconds, e.g., about 5 seconds or about 3 seconds.

Exemplary meters and test strips and using the same are shown in FIGS.6-10.

In certain embodiments, the glucose levels obtained by the AS system maynot be displayed or otherwise communicated to a user in real time, i.e.,the user of the system will be blinded to the data obtained—at least inreal time. Stated otherwise, no glucose results are shown on the ASsystem. The AS data will thus be retrospective providing blind data, andwill include a device (wired or wireless) so that an HCP device maydownload retrospective continuous glucose monitoring system data fromthe AS system for review and analysis. In certain embodiments, the ASsystem will not be calibrated in real time, e.g., will not include (orwill not include a functional or the strip port will be blocked) stripport to accept a calibration test strip. An in vitro system may be usedconcurrently with the system, and the data obtained by the in vitrosystem reviewed and used in the review and/or processing of AS data. Forexample, the in vitro data may be used to retrospectively calibrate theCG data, e.g., at a remote site such as an HCP site, and as shown, forexample, in FIG. 11.

Referring to FIG. 11, in one aspect, a user wears and uses an AS systemthat includes an in vivo analyte sensor (not shown) coupled to an ASdata processing unit (transmitter) worn (in this embodiment) on theuser's arm, and an AS receiver unit to receive information from the ASdata processing unit (wired or wirelessly). A blood glucose (“BG”) or invitro meter (used interchangeably) is also used and is configured totransfer data to a remote site such as shown here an HCP PC terminal(either wirelessly or otherwise). Also included is a data managementsystem (“DMS”). There is no data transfer connection between the invitro meter and the AS system, data transfer exists between the ASsystem and a DMS, such as a PC-based DMS.

In the particular embodiment of FIG. 11, in vitro data is transferred tothe HCP PC terminal via USB connection. The PC terminal may be at theuser's location, at which the data may then be accessed by the HCP(e.g., via a network connection, server connection or otherwise), ordownloaded to a computing device at the remote location. Once the HCPcollects AS data (which may be transferred to the HCP as raw data or maybe processed at least in certain respects), the data may be reviewedand/or further processed. For example, the AS data may be calibratedusing the collected in vitro data. The calibrated AS data may then bereviewed and/or processed further. For example, reports may begenerated. A data management system may be employed, e.g., such as theCoPilot™ data management system available from Abbott Diabetes Care,Inc., or analogous system. The HCP PC terminal may generate and reviewreports produced using the AS data.

Accordingly, in certain embodiments an HCP attaches the AS processingunit with transmitter to the user at the HCP office and provides areusable receiver unit to the user. The user may wear and collect datawith the AS receiver and transmitter for about one or more days, e.g.,about 2-30 days, e.g., about 3-7 days, e.g., about 5-7 days. The userperforms BG tests on their in vitro meter at appropriate times, e.g., at1, 2, 10, 24 and/or 72 hours after AS sensor insertion in certainembodiments. The user brings the AS receiver unit and in vitro meter tothe HCP office and the HCP connects the in vitro meter via a USB cable(or otherwise including wirelessly) to a computing device such as the PCterminal and downloads the in vitro data from the meter's memory. The ASreceiver wirelessly (or otherwise) transmits data to the PC. The HCP mayview the AS and/or BG information using a DMS loaded and running on theHCP PC terminal.

In one aspect, the data obtained by the in vitro meter includes a timestamp based, for example, from an internal clock. The in vitro meter inone aspect may be synchronized with the clock of the PC terminal so thatwhen the time stamped blood glucose values are received from the invitro meter, the time of day information associated with each bloodglucose test and the resulting blood glucose values are timesynchronized with the corresponding analyte data in the PC terminal forfurther processing and analysis. In this manner, improved accuracy maybe obtained. Further, the transmitted blood glucose values from the invitro meter may also be associated with the unique identifier of the invitro meter. In this manner, each blood glucose value derived orobtained from the in vitro meter will identify the corresponding invitro meter based on its unique identifier.

In this manner, in one aspect, the user may be provided with limited orno real time data from the AS receiver during the time the glucose datais collected from the user. As such, user behavior or health care ortreatment based decisions are limited or avoided by not allowing theuser to view the on-going continuous glucose level monitored by the ASsensor and collected by the AS system. In one aspect, the AS system maybe configured to provide limited output information to the user duringthe data collection modes, such as an indication that the AS system isfunctioning properly (for example, with periodic audible alerts, visualdisplays indicating system integrity, and the like). Other informationmay likewise be displayed or output on the AS receiver to the user suchas, for example, the time of day information, the duration of the datacollection elapsed, and so on.

Certain embodiments include prospective calibration of AS data, andunblinded AS data. An exemplary embodiment of such a system is shown inFIG. 12. This embodiment includes an AS data processing unit thatincludes a transmitter worn and used by a user, an AS receiving unit, anin vitro meter capable of transferring data to the AS system, (hereinshown using a wired connection, but wireless may also be used), and aDMS. Accordingly, in this embodiment, glucose results of the AS systemare communicated to the user in real-time, e.g., audibly and/or visuallysuch as on a display. There is unidirectional transfer of data from thein vitro blood glucose meter to the AS receiver, e.g., using a USB cableor the like. In certain embodiments, the transfer of data may bebidirectional so the BG meter could (for example) display the mostrecent CG data. This would greatly enhance the value of the BG meter (tobe able to display glucose data without the pain of drawing the blood),and more generally the BG meter may be used as a display unit formedical data besides just BG. For example, this may be included in aData Logger embodiment. The embodiment of FIG. 12 can be configured toshow or not show (“blind”) CG data since it uses prospective data.

Accordingly, in certain embodiments an HCP attaches the AS processingunit with transmitter to a user at the HCP office and provides a loaneror reusable AS receiver. The user may wear and collect data with the ASreceiver and transmitter for about one or more days, e.g., about 2-30days, e.g., about 3-7 days, e.g., about 5-7 days. The user performs BGtests on their in vitro meter at appropriate times, e.g., at 10, 24 and72 hours after AS sensor insertion in certain embodiments. When the userperforms a BG test on their in vitro meter, the user couples (wired orwirelessly) the meter to the AS receiver. The AS receiver may becalibrated using this transferred BG data. The user brings the ASreceiver and in vitro meter to the HCP office. The AS receiverwirelessly (or otherwise) transmits data to the PC. The HCP may view theAS and/or BG information using a DMS.

Certain embodiments include prospective calibration of AS data,unblinded data and an RF module. An exemplary embodiment of such asystem is shown in FIG. 13. This embodiment includes an AS dataprocessing unit that includes a transmitter worn and used by a user, anAS receiving unit, an in vitro meter capable of transferring data to theAS system, herein shown using a wired connection, (but wireless may alsobe used), an RF module, and a DMS. Accordingly, in this embodimentglucose results of the AS system are communicated to the user inreal-time, e.g., audibly and/or visually such as on a display. As shown,there is unidirectional transfer of data from the in vitro blood glucosemeter to the AS receiver, e.g., using RF and a wireless adaptor coupledto the in vitro meter. However, there may be bidirectional transfer ofdata that permits the in vitro meter to display AS data (i.e., the invitro meter including functionality to output the continuous analytesensor data).

Accordingly, in certain embodiments an HCP attaches the AS processingunit with transmitter to a user at the HCP office and provides a loaneror reusable AS receiver. The user may wear and collect data with the ASreceiver and transmitter for about one or more days, e.g., about 2-30days, e.g., about 3-7 days, e.g., about 5-7 days. The user performs BGtests on their in vitro meter at appropriate times, e.g., at 10, 24 and72 hours after AS sensor insertion in certain embodiments. When the userperforms a BG test on their in vitro meter, the wireless adapter willhave to be coupled to the meter and the BG test data may be wirelesslysent to the AS receiver. The collected data in the AS receiver may becalibrated using this transferred BG data. The user brings the ASreceiver and in vitro meter to the HCP office. The AS receiverwirelessly (or otherwise) transmits data to the PC. The HCP may view theAS data and/or BG information using a DMS.

Certain embodiments include unblinded, retrospective data and a USBcable. An exemplary embodiment of such a system is shown in FIG. 14.This embodiment includes a Data Logger, a USB cable, a serial cable toData Logger and an enhanced BG meter having continuous glucosemonitoring functionalities. Accordingly, in this embodiment continuousglucose monitoring capabilities are accorded with the in vitro meter,which includes a mini usb port. A user wears the Data Logger and mayview the retrospective data obtained by the Data Logger on the in vitrometer. There is unidirectional transfer (wired or wireless) of data fromData Logger to the BG meter—or may be bidirectional to allow calibrationof the CG data with BG data as well as to display CG data on the BGmeter.

Accordingly, in certain embodiments an HCP attaches an in vivo sensorand Data Logger to a user at the HCP office. The user may wear andcollect data with the Data Logger (for example, provided in the AStransmitter coupled to the in vivo sensor) for about one or more days,e.g., about 2-30 days, e.g., about 3-7 days, e.g., about 5-7 days. Theuser connects the USB cable from the Data Logger to the BG meter todownload results. The user brings the BG meter to the HCP site andtransits data, e.g., via usb cable, from the BG meter to the HCP PC orcomputer terminal. The HCP may view the Data Logger and/or BGinformation using a DMS.

Certain embodiments include unblinded, prospective data and a wirelessadapter. An exemplary embodiment of such a system is shown in FIG. 15.This embodiment includes a BG meter, an RF module and a Data Logger. TheBG meter is an enhanced BG meter having continuous glucose monitoringfunctionalities and a USB port. A user wears a Data Logger and can viewprospective data of the Data Logger on the BG meter. There isbidirectional transfer (wired or wireless) of data from Data Logger tothe BG meter.

Accordingly, in certain embodiments an HCP attaches an in vivo sensorand Data Logger to a user at the HCP office. The user may wear andcollect data with the Data Logger and transmitter for about one or moredays, e.g., about 2-30 days, e.g., about 3-7 days, e.g., about 5-7 days.The user connects the wireless adapter to the BG meter to downloadresults. The user brings the BG meter to the HCP site and transits data,e.g., via the wireless adapter, from the BG meter to the HCP pc. HCP mayview the Data Logger and/or BG information using a DMS.

In certain embodiments, an AS receiver unit may be embedded in a BGmeter. That is, the BG meter may be configured to directly communicatewith the AS transmitter and to receive/store data from the AStransmitter and collect the monitored glucose levels from the in vivosensor.

While in the embodiments described above, specific implementation ofdata communication including wired or cabled and wireless, and dataprocessing is described, within the scope of the present disclosure,other data communication techniques may be used including wired over acable connection and/or wireless over a communication link such as RFcommunication link, infrared communication link, Bluetooth®communication link, and the like, as well as networked datacommunication over data networks such as, but not limited to local areanetwork, wide area network, metropolitan area network and the like,using data protocols such as, but not limited to TCP/IP, InternetProtocol version 4 (IPv4), Internet Protocol version 6 (IPv6), wirelessapplication protocol (WAP), and the like. 4 (IPv4), Internet Protocolversion 6 (IPv6), wireless application protocol (WAP), and the like.

FIG. 16 shows a table of exemplary embodiments and respective featuresthat may be included. Any feature may be combined with any otherembodiment, and/or features may be removed and/or added from/to anyembodiment.

In one aspect, a data management system may generate a variety ofreports, including 3 and/or 5 and/or 7 day reports of AS data and/or BGdata. In certain embodiments, all or substantially all data processingis performed by the DMS, e.g., calibration of AS data, data analysis,mining, aggregation, filtering, and other suitable or desirable dataprocessing functions including for example, therapy based analysis.

Data may be encrypted/decrypted and/or password protected forcommunication or transfer over one or more data networks or using one ormore data communication protocol described above, for example.Additionally, data integrity and validation may be performed, forexample, for detecting and/or correcting errors in the transmitted datausing, for example, but not limited to, cyclic redundancy code (CRC),Manchester encoding/decoding, and the like. The AS system may include aunique identifier which may be known at the remote site (e.g., by theHCP system), to ensure data is correctly attributed to the correct userat the HCP site. Embodiments include various patient privacyprotections, e.g., in accordance with Health Information Protection Act(HIPPA). In other words, systems herein may be HIPPA compliant.

In certain embodiments, data may be directly, e.g., automatically,transferred into a user's medical records (electronic record), billingdata, etc. e.g., from the DMS. Embodiments include those capable tocomplete seamless downloads to electronic medical records systems. Incertain embodiments, a reimbursement code may be automaticallydetermined by the system for the HCP, e.g., Medical and/or Medicaidand/or various state codes. Determining such codes may be time consumingand complex. An analyte system that performs this task would be a greatbenefit to HCPs and users. For example, a reimbursement code may bedetermined by a system such as a DMS and displayed audibly and/orvisually on a user interface display. The code may be automaticallyentered into a patient's records and/or reimbursement files and“paperwork”. Embodiments include those capable to complete seamlessidentification of reimbursement code(s) and/or download such to one ormore compatible electronic systems. Accordingly, certain embodiments areself-documenting.

As noted above, embodiments are configured to ensure patient privacy,e.g., are HIPPA compliant. For example, as described above someembodiments include components that may be used by more than oneindividual. Patient data may be patient identification (ID) identifiedand all patient data from a first user may be automatically deleted fromthe system or one or more system components when the system isconfigured for a second user, e.g., by an HCP. For example, an AS dataprocessing unit and/or receiving unit may require an initializationprocedure for each use or user, e.g., performed by an HCP or the user,which requires entry of a password or other unique patient identifier.Patient specific data may be automatically deleted or the initializermay be prompted to delete during initialization of the CG system.Likewise, patient specific data may be scrambled, encrypted, orotherwise rendered indiscernible. Patient data may be deleted based on atime schedule in certain embodiments.

The AS systems and methods may be applicable for Type I and Type IIdiabetics, newly diagnosed diabetics, patients experiencing diabeticcondition, post surgery glycemic control and the like. The AS systemsand methods may be used in conjunction with multiple users or patients,for data analysis or therapy management.

The components of the embodiments herein may be combined in a singlehousing or may be separate. Further, embodiments may be re-usable, suchthat, they may be used by a plurality of users. In certain embodiments,DMS may be a PC based application, e.g., a Windows application.

Embodiments may include a module that (1) supports bidirectional orunidirectional RF (or infrared “IR”, or Bluetooth®) communicationbetween the module and a CG transmitter unit and/or Data Logger, and/or(2) communicates to a BG meter via a wired connection (such as a cableor set of contacts), (3) communicates to a data processing terminal suchas a PC (e.g., unit 105) via RF, IR or a wired cable, and/or contains amicroprocessor (CPU) to handle all of the communication and dataprocessing tasks.

For example, a module may serve as a communications hub between a BGmeter, a PC and a CG transmitter or Data Logger, thereby enabling CG-BGcalibration, the display of CG data on the BG meter, data transfer to aDMS, and data collection for retrospective or prospective analysis. Byhaving this capability, the overall system is very cost effective andeasy to use since the display and BG capabilities of the BG meter aren'tduplicated elsewhere in the system, and the overall system would havecomplete CG functionality without adding any significant extra cost tothe base HCP meter.

Accordingly, an analyte monitoring device such as an assessor in oneembodiment may include a data collection module for receiving andstoring analyte data over a predetermined time period from a subject, auser interface unit coupled to the data collection module for providingone or more indication related to the analyte data, a control unitcoupled to the data collection module and the user interface unit tocontrol, at least in part the operation of the data collection moduleand the user interface unit, and a communication module coupled to thecontrol unit for communicating one or more signals associated with theanalyte data to a remote location, where the user interface unit isconfigured to operate in a prospective analysis mode includingsubstantially real time output of the analyte level received by the datacollection module, and a retrospective analysis mode including limitedoutput of information to the subject during the predetermined timeperiod, and further where the communication module is configured tocommunicate with the remote location after the analyte data is receivedand stored in the data collection module over the predetermined timeperiod.

The device may include a strip port operatively coupled to the controlunit for receiving a blood glucose test strip.

The communication module in one embodiment may be configured tocommunicate with the remote location using one or more of a USB cableconnection, a serial cable connection, an RF communication protocol, aninfrared communication protocol, a Bluetooth® communication protocol, oran 802.11x communication protocol.

The user interface unit may be configured to not display any informationrelated to the received analyte data in the retrospective analyte mode.

In one aspect, the limited output of information during theretrospective analysis mode may include output to the user interfaceunit of one or more of the analyte monitoring device operational statusinformation, a time of day information, a user profile information, orthe elapsed duration of the predetermined time period.

The data collection module may include one or more of a data storagedevice or a memory device, where the memory device may be a randomaccess memory.

In another aspect, the data collection module may be configured todelete the stored analyte data after transferring the analyte data tothe remote location.

The remote location may include a data processing terminal such as anHCP PC terminal.

In a further aspect, during the prospective analysis mode, the userinterface unit may be configured to visually output real timeinformation related to the received analyte data of the subject, wherethe visual output may include one or more of a graphical output, anumerical output, or a text output.

The stored analyte data in the data collection module may beuncalibrated.

The communicated one or more signals associated with the analyte data tothe remote location may include uncalibrated analyte data.

In a further aspect, the communication module may be configured toreceive one or more calibration information, where the calibrationinformation may include blood glucose data.

Also, the control unit may be configured to calibrate the received andstored analyte data based on the received calibration information togenerate calibrated analyte data, where the data collection module maybe configured to store the calibrated analyte data.

Further, the communication module may be configured to transmit thecalibrated analyte data to the remote location.

A method in another embodiment may include storing analyte data over apredetermined time period received from a subject, providing one or moreindication related to the received analyte data on a user interfaceunit, including operating the user interface unit in a prospectiveanalysis mode including substantially real time output of the analytelevel received by the data collection module, and a retrospectiveanalysis mode including limited output of information to the subjectduring the predetermined time period, and communicating one or moresignals associated with the analyte data to a remote location after theanalyte data is received and stored over the predetermined time period.

The method in another aspect may include receiving a blood glucose testdata.

The method may also include communicating with the remote location usingone or more of a USB cable connection, a serial cable connection, an RFcommunication protocol, an infrared communication protocol, a Bluetooth®communication protocol, or an 802.11x communication protocol.

The method may include not displaying any information related to thereceived analyte data in the retrospective analyte mode.

The limited output of information during the retrospective analysis modemay include outputting one or more of an operational status information,a time of day information, a user profile information, or the elapsedduration of the predetermined time period.

In still another aspect, the method may include deleting the storedanalyte data after transferring the analyte data to the remote location.

Also, during the prospective analysis mode, the method may includevisually outputting real time information related to the receivedanalyte data of the subject, where the visual output may include one ormore of a graphical output, a numerical output, or a text output.

In another aspect, the stored analyte data may be uncalibrated.

The method may include transmitting uncalibrated analyte data to theremote location.

Further, the method in yet another aspect may include receiving one ormore calibration information, where the calibration information mayinclude blood glucose data.

In yet a further aspect, the method may include calibrating the receivedand stored analyte data based on the received calibration information togenerate calibrated analyte data.

The method may also include storing the calibrated analyte data.

Additionally, the method may include transmitting the calibrated analytedata to the remote location.

In yet a further aspect, the in vitro blood glucose meter may beconfigured to output or otherwise display the analyte sensor data, wherethe blood glucose meter includes a memory unit such as random accessmemory or other similar storage unit to store the analyte sensor data(which may be a one minute analyte related data over a time period ofone to seven days, for example). Other time periods for the storage ofanalyte related data may be contemplated including, for example, longerthan seven days, and further, the each analyte related data may be afive minute data or 10 minute data, for example.

In another aspect, the clocks in the in vitro blood glucose meter andthe receiver unit (FIG. 1) may be time synchronized initially or duringuse, or periodically, such that the blood glucose value obtained by thein vitro blood glucose meter has a time corresponding analyte sensordata from the analyte sensor 101 (FIG. 1).

Various other modifications and alterations in the structure and methodof operation of the present disclosure will be apparent to those skilledin the art without departing from the scope and spirit of the presentdisclosure. Although the present disclosure has been described inconnection with specific embodiments, it should be understood that thepresent disclosure as claimed should not be unduly limited to suchspecific embodiments. It is intended that the following claims definethe scope of the present disclosure and that structures and methodswithin the scope of these claims and their equivalents be coveredthereby.

What is claimed is:
 1. An analyte monitoring device, comprising: a datacollection module for receiving and storing analyte data over apredetermined time period; a user interface unit coupled to the datacollection module for providing one or more indication related to theanalyte data; a control unit coupled to the data collection module andthe user interface unit, and configured to control, at least in part anoperation of the data collection module and the user interface unit; anda communication module coupled to the control unit for communicating oneor more signals associated with the analyte data to a remote location;wherein the user interface unit is configured to operate in aprospective analysis mode including substantially real time output of ananalyte level received by the data collection module, and aretrospective analysis mode including limited output of informationduring the predetermined time period; wherein the communication moduleis configured to communicate with the remote location after the analytedata is received and stored in the data collection module over thepredetermined time period; and wherein the data collection module isoperatively coupled to a transcutaneously positioned analyte sensor influid contact with an interstitial fluid under a skin layer, the analytesensor generating signals corresponding to a monitored analyte levelover the predetermined time period, wherein when the user interface unitis operating in the retrospective analysis mode, the user interface unitis configured to not display any information related to the receivedanalyte data during the predetermined time period.
 2. The device ofclaim 1 wherein the communication module is configured to communicatewith the remote location using one or more of a USB cable connection, aserial cable connection, a radio frequency (RF) communication protocol,an infrared communication protocol, a Bluetooth communication protocol,or an 802.11x communication protocol.
 3. The device of claim 1 whereinthe limited output of information during the retrospective analysis modeincludes output to the user interface unit of one or more of the analytemonitoring device operational status information, a time of dayinformation, a user profile information, or an elapsed duration of thepredetermined time period.
 4. The device of claim 1 wherein the datacollection module includes one or more of a data storage device or amemory device.
 5. The device of claim 1 wherein the data collectionmodule is configured to delete the stored analyte data aftertransferring the analyte data to the remote location.
 6. The device ofclaim 1 wherein the remote location includes a data processing terminal.7. The device of claim 1 wherein during the prospective analysis mode,the user interface unit is configured to visually output real timeinformation related to the received analyte data.
 8. The device of claim7 wherein the visual output includes one or more of a graphical output,a numerical output, or a text output.
 9. The device of claim 1 whereinthe stored analyte data in the data collection module are uncalibrated.10. The device of claim 1 wherein the communicated one or more signalsassociated with the analyte data to the remote location includesuncalibrated analyte data.
 11. The device of claim 1 wherein thecommunication module is configured to receive one or more calibrationinformation.
 12. The device of claim 11 wherein the calibrationinformation includes blood glucose data.
 13. The device of claim 11wherein the control unit is configured to calibrate the received andstored analyte data based on the received calibration information togenerate calibrated analyte data.
 14. The device of claim 13 wherein thedata collection module is configured to store the calibrated analytedata.
 15. The device of claim 13 wherein the communication module isconfigured to transmit the calibrated analyte data to the remotelocation.
 16. The device of claim 1 wherein the analyte sensor comprisesa plurality of electrodes including a working electrode, and furtherwherein the working electrode comprises an analyte-responsive enzyme anda mediator.
 17. The device of claim 16 wherein at least one of theanalyte-responsive enzyme and the mediator is chemically bonded to apolymer disposed on the working electrode.
 18. The device of claim 17wherein at least one of the analyte-responsive enzyme and the mediatoris crosslinked with the polymer.
 19. A method, comprising:transcutaneously positioning an analyte sensor in fluid contact withinterstitial fluid under a skin layer; generating analyte data based onsignals from the analyte sensor, the analyte data corresponding to amonitored analyte level over a predetermined time period; storing theanalyte data corresponding to the monitored analyte level over thepredetermined time period; providing one or more indication related tothe analyte data on a user interface unit, including operating the userinterface unit in a prospective analysis mode including substantiallyreal time output of the monitored analyte level, and a retrospectiveanalysis mode including limited output of information during thepredetermined time period; and communicating one or more signalsassociated with the analyte data to a remote location after the analytedata is generated and stored over the predetermined time period; whereinwhen the user interface unit is operating in the retrospective analysismode, the user interface unit is configured to not display anyinformation related to the received analyte data during thepredetermined time period.
 20. The method of claim 19 includingcommunicating with the remote location using one or more of a USB cableconnection, a serial cable connection, a radio frequency (RF)communication protocol, an infrared communication protocol, a Bluetoothcommunication protocol, or an 802.11x communication protocol.
 21. Themethod of claim 19 wherein the limited output of information during theretrospective analysis mode includes outputting one or more of anoperational status information, a time of day information, a userprofile information, or an elapsed duration of the predetermined timeperiod.
 22. The method of claim 19 including deleting the stored analytedata after transferring the analyte data to the remote location.
 23. Themethod of claim 19 including, during the prospective analysis mode,visually outputting real time information related to the analyte data.24. The method of claim 23 wherein the visual output includes one ormore of a graphical output, a numerical output, or a text output. 25.The method of claim 19 wherein the stored analyte data are uncalibrated.26. The method of claim 19 including transmitting uncalibrated analytedata to the remote location.
 27. The method of claim 19 includingreceiving one or more calibration information.
 28. The method of claim27 including calibrating the generated and stored analyte data based onthe received calibration information to generate calibrated analytedata.
 29. The method of claim 28 including storing the calibratedanalyte data.
 30. The method of claim 28 including transmitting thecalibrated analyte data to the remote location.
 31. The method of claim19 wherein the analyte sensor comprises a plurality of electrodesincluding a working electrode, and further wherein the working electrodecomprises an analyte-responsive enzyme and a mediator.
 32. The method ofclaim 31 wherein at least one of the analyte-responsive enzyme and themediator is chemically bonded to a polymer disposed on the workingelectrode.
 33. The method of claim 32 wherein at least one of theanalyte-responsive enzyme and the mediator is crosslinked with thepolymer.